The present invention relates to apparatus and methods for treating eyes, such as eyes of mammals having eye disorders or diseases, more particularly to apparatus and methods for administering a therapeutic medium or agent intravitreously, yet more particularly to apparatus and methods for administering such therapeutics or agents to the tissues of the eye so that the pharmaceutical action of the such therapeutics/agents is localized at the choroid and the retina, or at the ciliary body or the lens.
There are a number of vision-threatening disorders or diseases of the eye of a mammal including, but not limited to diseases of the retina, retinal pigment epithelium (RPE), ciliary body, lens and choroid. Such vision threatening diseases include, for example, ocular neovascularization, ocular inflammation and retinal degenerations. Specific examples of these disease states include diabetic retinopathy, glaucoma, chronic glaucoma, posterior capsule opacification, retinal detachment, sickle cell retinopathy, age-related macular degeneration, retinal neovascularization, subretinal neovascularization; rubeosis iritis inflammatory diseases, chronic posterior and pan uveitis, neoplasms, retinoblastoma, pseudoglioma, neovascular glaucoma; neovascularization resulting following a combined vitrectomy and lensectomy, vascular diseases, retinal ischemia, choroidal vascular insufficiency, choroidal thrombosis, neovascularization of the optic nerve, diabetic macular edema, cystoid macular edema, macular edema, retinitis-pigmentosa, retinal vein occlusion, proliferative vitreoretinopathy, angioid streak, and retinal artery occlusion, and, neovascularization due to penetration of the eye or ocular injury.
A number of techniques or methodologies have been developed to deliver drugs to the various eye tissues or structure to treat a wide range of these disorders or diseases. However, delivery of drugs, proteins and the like to the eye(s) of mammals so as to achieve the desired therapeutic or medical effect, especially to the retina and/or the choroids, has proven to be challenging, most of which is owed to the geometry, delicacy and/or behavior of the eye and its components. A brief description of various conventional methods or techniques for delivering drugs to the tissues of the eye and the shortcomings thereof are hereinafter described.
Oral ingestion of a drug or injection of a drug at a site other than the eye can provide a drug systemically however such a systemic administration does not provide effective levels of the drug specifically to the eye. In many ophthalmic disorders involving the retina, posterior tract, and optic nerve, adequate levels of the drug cannot be achieved or maintained by oral or parenteral routes of administration. Thus, further and repeated administration of the drug would be necessary to achieve the desired or adequate levels of concentration of the drug. Such further and repeated administrations of such drugs, however, may produce undesired systemic toxicity.
Ophthalmic conditions have also been treated using drugs applied directly to the eye in either liquid or ointment form. This route of administration (i.e., topical administration), however, is only effective in treating problems involving the superficial surface of the eye and diseases that involve the cornea and anterior segment of the eye, such as for example, conjunctivitis. Topical administration of drugs is ineffective in achieving adequate concentrations of a drug(s) in the sclera, vitreous, or posterior segment of the eye. In addition, topical eye drops may drain from the eye through the nasolacrimal duct and into the systemic circulation, further diluting the medication and risking unwanted systemic side effects. Furthermore, delivery of drugs in the form of topical eye drops is also of little utility because the drug cannot cross the cornea and be made available to the vitreous, retina, or other subretinal structures such as the retinal pigment epithelium (“RPE”) or choroidal vasculature and/or is highly unstable and therefore not easily formulated for topical delivery. Moreover, data also indicates that it is not unusual for up to 85% of topically applied agents to be removed by the eye's blink mechanism/reflex.
Direct delivery of drugs to the eye by a topical insert has also been attempted however this method is not desirable. Such topical inserts require patient self-administration and thus education on their insertion into and removal from the eye. Consequently, this technique demands a certain degree of manual dexterity that can be problematic for geriatric patients who are particularly susceptible to certain eye disorders that appear age related (e.g., age related macular degeneration). Also, in many instances such topical inserts may cause eye irritation and such inserts are prone to inadvertent loss due to eyelid laxity. In addition, these devices provide a source of drug only to the cornea and anterior chamber, and thus do not provide any pharmacologic advantage over topical eye drops or ointments. Thus, such devices have limited, if any at all, utility for providing an effective source of drugs to the vitreous or tissues located in the posterior segment of the eye.
As a consequence most methods for treating eye disorders or diseases in the posterior segment, or the back-of-the-eye, involve intraocular (and more specifically intravitreal) delivery of the drug. One such technique for intravitreal delivery is accomplished by intraocular injection of the drug or microspheres containing the drug directly into the vitreous or by locating a device or capsule containing the drug in the vitreous, such as that described in U.S. Pat. No. 5,770,589.
Intraocular injection is commonly used in ophthalmology for delivering therapeutics or agents (e.g. drugs of interest) to the posterior segment of the eye, especially when it is useful to deliver high concentrations of drugs. Such an operation is used in particular for injecting compositions comprising for example corticosteroids or neovascularization inhibitors in the vitreous body of the eye, in order to treat diseases affecting retina or choroids, or ciliary body or lens.
Intraocular injection procedure generally consists in:
moving apart the eyelids with an eyelids retractor,
locating an injection area on the eye using a compass,
introducing the needle into the eye at the level of the injection area, and
injecting a composition via the needle and removing the needle while pressing the superficial layers of the eye in the injection area in order to limit the risk of leakage of the injected substance.
Such a procedure requires high technical skills and lots of practice. For this reason, many non-qualified ophthalmologists are not able to carry out such operations.
In particular, the injection area must be precisely defined. In order to avoid damaging structures located in front of the vitreous body (such as cornea, iris and lens crystalline) and structures located at the rear of the vitreous body (such as retina), the needle is generally introduced at a given distance, usually around 3 to 4 mm, from the limbus zone, which is a transition zone extending between the cornea and the sclera. The depth of penetration of the needle into the eye must also be carefully controlled.
Additionally, precautions must be taken in order to limit risks of complications due to perforation of eye tissues. In particular, perforation of the tissues can cause leakage of the injected composition out of the eye though the orifice created by the needle. This phenomenon prevents the ophthalmologist from controlling the amount of active compound that has been actually introduced into the eye. Moreover, perforation of the tissues can also favour penetration of germs into the eye, causing ocular infections.
Document WO 01/49226 discloses an apparatus for facilitating intraocular injection, comprising a plaque which is adapted to be positioned over an eye of a patient so as to be centred on the iris. The plaque has apertures for guiding a syringe needle into the eye. The inner surface of the plaque which contacts the eye is equivalent to the exposed surface of the eye when substantially open. This document mentions that the positioning of the plaque may be aided for example by a ring on the plaque showing the border between the iris and the sclera.
However, such an apparatus is not very easy to handle, as the ophthalmologist must maintain the apparatus with one hand while operating the syringe with the other hand. Moreover, in such an apparatus, the plaque is necessarily bulky, as it must covers all the exposed surface of the eye. And the positioning of such an apparatus necessitates that the eyelids be retracted. And finally, as the plaque is centred on the iris, the apparatus is not adapted to an eye having a cornea of non-standard diameter.